Abstract
Introduction: The NMDA receptor antagonist, phencyclidine (PCP) induces behavioural changes in rodents which mimic schizophrenia symptoms, and provides a well validated model of the disease[1]. These effects are reversed by dopamine D4 receptor agonists[2], including A412997 (N-(3-Methylphenyl)-4-(2-pyridinyl)-1-piperidineacetamide). The current study aimed to assess the effect of PCP pretreatment on the A412997-mediated attenuation of electrically-stimulated dopamine release in rat brain slices.
Method: Newly weaned (3-4 weeks) female Wistar rats were pretreated (i.p.) with either PCP (2 mg/kg) or saline (1 ml/kg) twice daily for 5 days followed by a 7 day drug-free period. They were humanely killed, brains were removed and consecutive 400 μm slices were cut using a vibrotome, and equilibrated in oxygenated aCSF ((mM) NaCl(126), KCl(2.5), NaH2PO4(1.2), NaHCO3(25), MgCl2(1.2), CaCl2(2.4), d-glucose(11), 1-ascorbate(0.4)) at room temperature. Following equilibration for at least 60 min, a slice was placed in the tissue chamber and superfused with oxygenated aCSF (33±1°C). A pair of tungsten stimulating electrode, and a carbon fibre voltammetry electrode were placed in nucleus accumbens shell (NAcS). Fast cyclic voltammetry recordings were made by applying a potential waveform (-0.4 to +1.3 to -0.4 V; 400 V/s), and dopamine was measured in the background subtracted current signal at an applied voltage of 600 mV. Ten electrical stimulation trains (10 pulses; 300 μA, 4ms, 60 Hz) were applied at 3 minute intervals. After 2 baseline stimulation, A412997 (2 μM) was included in the superfusate for four stimulations (12 min) (control slices received no drug). A further four post drug (washout) stimulations were applied.
Results: Statistical analysis (ANOVA) showed a significant main effect of drug (F[3,26] = 4.346, P < 0.05) and a significant drug x time interaction (F[6,52] = 2.781, P < 0.05). Post hoc analysis showed that the attenuation of stimulated dopamine release produced by A412997 was completely absent in slices from PCP pretreated animals.
Conclusion: Application of the dopamine D4 agonist, A412997, caused a decrease in electrically stimulated dopamine release in NAcS, which was entirely abolished in animals pretreated with PCP, in a model of schizophrenia. These changes are important in understanding of the role of dopamine D4 receptors in animal models of schizophrenia.
References:
1. Sood et al., (2011). J. Psychopharmacol 25, 792-800
2. Grayson et al. (2014). Behavioural Brain Research 266; 188-192.
Method: Newly weaned (3-4 weeks) female Wistar rats were pretreated (i.p.) with either PCP (2 mg/kg) or saline (1 ml/kg) twice daily for 5 days followed by a 7 day drug-free period. They were humanely killed, brains were removed and consecutive 400 μm slices were cut using a vibrotome, and equilibrated in oxygenated aCSF ((mM) NaCl(126), KCl(2.5), NaH2PO4(1.2), NaHCO3(25), MgCl2(1.2), CaCl2(2.4), d-glucose(11), 1-ascorbate(0.4)) at room temperature. Following equilibration for at least 60 min, a slice was placed in the tissue chamber and superfused with oxygenated aCSF (33±1°C). A pair of tungsten stimulating electrode, and a carbon fibre voltammetry electrode were placed in nucleus accumbens shell (NAcS). Fast cyclic voltammetry recordings were made by applying a potential waveform (-0.4 to +1.3 to -0.4 V; 400 V/s), and dopamine was measured in the background subtracted current signal at an applied voltage of 600 mV. Ten electrical stimulation trains (10 pulses; 300 μA, 4ms, 60 Hz) were applied at 3 minute intervals. After 2 baseline stimulation, A412997 (2 μM) was included in the superfusate for four stimulations (12 min) (control slices received no drug). A further four post drug (washout) stimulations were applied.
Results: Statistical analysis (ANOVA) showed a significant main effect of drug (F[3,26] = 4.346, P < 0.05) and a significant drug x time interaction (F[6,52] = 2.781, P < 0.05). Post hoc analysis showed that the attenuation of stimulated dopamine release produced by A412997 was completely absent in slices from PCP pretreated animals.
Conclusion: Application of the dopamine D4 agonist, A412997, caused a decrease in electrically stimulated dopamine release in NAcS, which was entirely abolished in animals pretreated with PCP, in a model of schizophrenia. These changes are important in understanding of the role of dopamine D4 receptors in animal models of schizophrenia.
References:
1. Sood et al., (2011). J. Psychopharmacol 25, 792-800
2. Grayson et al. (2014). Behavioural Brain Research 266; 188-192.
| Original language | English |
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| Publication status | Published - 11 Dec 2017 |
| Event | Annual Pharmacology Meeting: The British Pharmacological Society - London, United Kingdom Duration: 11 Dec 2017 → 13 Dec 2017 |
Conference
| Conference | Annual Pharmacology Meeting: The British Pharmacological Society |
|---|---|
| Country/Territory | United Kingdom |
| City | London |
| Period | 11/12/17 → 13/12/17 |